Acute lymphoblastic leukemia (ALL) is the most common childhood cancer and is a leading cause of cancer-related death. Although the outcome of children and adolescents with ALL has improved substantially in recent decades, up to 20% of patients will relapse. Among children with a bone marrow (BM) relapse within 36 months of diagnosis, 90% will die. Major advances in understanding the heterogeneity of biologic diseases that comprise ALL have contributed to modern risk stratification algorithms that emphasize the critical contributions of ALL genotype and early response to induction chemotherapy to assign post-induction therapies of different intensities. However, these algorithms are population-based and many children who fail current therapies have features that are indistinguishable at diagnosis from those are cured. Furthermore, except for the 3-4% of children with Philadelphia chromosome positive (Ph+) ALL, current treatments do not include molecularly targeted therapy. Collaborative genomics-based initiatives within the Children's Oncology Group (COG) have revealed previously unrecognized mutations and pathway alterations in childhood ALL that can serve as potential therapeutic targets. The childhood high risk (HR) ALL TARGET (Therapeutically Applicable Research to Generate Effective Treatments) pilot project performed comprehensive genomic analyses (Affymetrix U133 Plus2.0 gene expression profiles and 500k + 100k single nucleotide polymorphism (SNP) chip analyses) to characterize approximately 200 cases of patients with higher risk ALL treated uniformly on the legacy COG P9906 trial. This pilot project has yielded major new insights into ALL biology and identified new therapeutic targets associated with a very high risk of relapse, including Janus kinase (JAK) mutations, for which we are now developing clinical trials. The COG ALL committee is determined to incorporate these novel findings into clinical trials for children with ALL quickly. The current proposal is designed to 1) validate the key TARGET findings from COG P9906 on cohorts of children with standard risk (SR) and HR B-precursor ALL treated on contemporary COG ALL protocols, b) determine the optimal assays to identify patients at diagnosis who may be candidates for JAK inhibitor therapy, and c) implement clinical testing for these markers in real-time on consecutively diagnosed patients enrolled on current COG ALL trials. This indeed presents a "Grand Opportunity" and paradigm shift for the COG to improve therapy for childhood ALL by integrating molecularly targeted agents into traditional chemotherapy regimens, an approach which we have shown to be very effective in children with Ph+ ALL. PUBLIC HEALTH RELEVANCE: Leukemia remains a major cause of morbidity and mortality in childhood. The Children's Oncology Group Acute Lymphoblastic Leukemia Committee and their collaborators have discovered a new leukemogenic pathway that may be amenable to treatment with more targeted therapies. This would permit clinicians to cure more children of their leukemia and potentially spare others of the substantial late effects that occur with traditional chemotherapy.